Manufacture of pyridine-4.5-dicarboxylic acid compounds



Patented Apr. 4, 1944' MANUFACTURE OF PYRIDINE-LS-DICAR- BOXYLIC ACIDCOMPOUNDS Walter Salzer and Hans Henecka, Wnppertal-Elassignors toWinthrop Chemical Company, Inc., New York, N. Y.', a corporation of NewYork No Drawing. Application January 26, 1940, Serial No. 315,758.. InGermany February 8, 1939 berield, Germany,

Claims.

This invention relates to a process of preparing 2-methyl-3-alkoxypyridine-4.5-dicarboxylic acid compounds.

In accordance with the present invention 2-'methyl-3-alkoxy-pyrldine-4.5-dicarboxylic a c i d compounds areobtainable by nitrating s-alkoxyquinaldinei-carboxylic acids by means ofusual nitrating agents, whereby the nitro group enters into the benzenering of the quinaldine ring systom; thebz-nitro-3-alkoxyquinaldine-4-carboxylic acids are then reduced to thecorresponding amino compounds by means of reducing agents usual forconverting nitro into amino groups, the

bz-amino-3-alkoxyquinaldine-4-carboxylic acids thus obtainable are thenconverted into 2-methyl-3-alkoxypyridine-4.5;6-tricarboxylic acid byoxidation and the latter compounds are decarboxylated to the2-methyl-3-alkoxy-pyridine-4.5- dicarboxylic acids. The initialmaterials which are obtainable for instance by alkylating3-hydroxyquinaldine-d-carboxyiic acids and by saponification of the3-alkoxyquinaldine-4-carbox ylic acids primarily formed are nitrated,for instance, by means of usual nitrating mixtures of nitri] andsulfuric acid. The reduction of the nitro compound may be performed, forinstance, while using iron as the reducing agent. The oxidation of thebz-anfino-B-alkoxyquinaldine-4-carboxylic acids is preferably effectedby means of a permanganate in alkaline solution. The 2-methyl-3-alkoxy-pyridine-4.5.S-tricarboxylic acids are decarboxylated by heattreatment, advantageously by boiling the tricarboxylic acid with anorganic acid anhydride such as for instance acetic anhydride; upon suchtreatment the carboxylic group standing in 6-position is split oil andthe anhydride of the 2-methyl-3-alkoxy pyridine-4.5- dicarboxylic acidis formed. The 2-methyl-3- alkoxy pyridine-4.5.6-tricarboxylic acids mayalso be heated as such or in the presence of a diluent, such as forinstance acetic acid, phenols, polyhalogen benzenes or naphthalenes,paraflin oil or the like to temperatures above 100 C., preferably to atemperature from about 150 to about 250 C. until the development ofcarbon dioxide has finished. The 2-methyl-3-alkoxy pyridine-4.5-dicarboxylic acid anhydrides which may be primarily obtained uponsuch treatment may be transformed into the corresponding dicarboxylicacids by heating with water. The reaction may also be carried out with3-alkoxyquinaldine-4- carboxylic 'acids which are substituted in thebenzene ring by alkyl, halogen or further alkoxy groups, the saidsubstituents being lost in the oxidation stage. The starting materialsare obtainable from correspondingly substituted isatines according toGerman Patent 615,743.

The invention is illustrated by the following example without beingrestricted thereto:

Example 480 grams of 3-hydroxyquinaldine-4-carboxylic acid are coveredwith 4 liters of acetone. The mixture is heated to boiling and after theaddition of 730 grams of pulverized potassium carbonate while vigorouslystirring. Thereupon 615 grams of dimethylsulfate are slowly added dropby drop to the mixture within 2-3 hours; the mixture is then furtherheated for 2 hours. After cooling the acetone solution is separated fromthe salts, the acetone distilled ofi from the filtrate and the oilyresidue is purified by distillation in a high vacuo. The3-methoxyquinaldine-4-carboxylic acid methylester is thus obtained as alight-yellow, viscous oil which boils under 3 mms. pressure at 160 C.

231 grams of the above-mentioned ester are dissolved in 500 cos. ofalcohol. The mixture is heated to boiling after the addition of 375 cos.of 4-normal potassium hydroxide solution for 1 hour. After cooling ofthe mixture the alcohol is removed under reduced pressure and the 3-methoxyquinaldinel-carboxylic acid is precipitated from the coldalkaline solution by the addition of 375 ccs. of 4-normal hydrochloricacid in nearly colorless crystals; they are filtered with suction,washed with water and dried.

grams of the 3-methoxyquinaldine-4-carboxylic acid thus obtained areintroduced while cooling with ice-water into 300 cos. of concentratedsulfuric acid. A mixture of 50 grams of nitric acid (specificgravity=1.4) and cos. of concentrated sulfuric acid is added to thesolution while permanently cooling in such away that the temperaturedoes not exceed +10 C. After 1-2 hours standing the mixture-is poured onto finely divided ice and the acid is neutralized in the solution thusobtained by the addition of ammonia until it reacts neutral to Congo.The bz-nitro-3-methoxyquinaldine-4-carboxy1ic acid precipitating isfiltered with suction, washed with water and for reduction purposesgradually poured into a boiling mixture of 550 grams of iron, 770 cos.of water and 6-10 cos, of glacial acetic acid while vigorously stirring.Thereupon the solution is heated to boiling for 2 hours, the hotreaction mixture is treated with sodium hydroxide solution until it justreacts alkaline and filtered with suction while hot from iron sludge.The bz-amino-S-methoxyquinaldine-4-carboxylic acid is obtained from thefiltrate on treatment with dilute acetic acid as a light orange-red,finely crystalline mass which is filtered with suction and dried. Itmelts at 240 C. while foaming up.

ceed +10 C. When the addition has been :fin-

ished the solution is heated for a short time on the boiling water-bathand the hot solution freed from the manganese dioxide by means offiltration with suction. The manganese dioxide is extracted by boilingwith water several times and the barium precipitated from the unitedfiltrates as barium sulfate by the addition of a Just sufficiently greatquantity of dilute sulfuric acid. After the separation of the bariumsulfate the filtrate is evaporated to dryness under reduced pressure,whereupon the 2-methyl-3-methoxypyridine 4.5.6 tricarboxylic acidprecipitates from the concentrated solution -as a light-yellow finelycrystalline powder. The acid is rather readily soluble in water andglacial acetic acid, more diflicultly, however, in alcohol or acetone,insoluble in ether. The acid melts with decomposition at 205-215 C.

1 part by weight of the 2-methyl-3-methoxypyridine-4.5.6-tricarboxylicacid thus obtained is covered with the 10-fold quantity by weight ofacetic-anhydride. The mixture is heated to 2130- 135 C. until the acidis dissolved and the evolution of carbon dioxide has ceased. Thesolution thus obtained is evaporated under reduced pressure, the residuedissolved in chloroform, the solution freed from undissolved impuritiesby filtration, and the chloroform evaporated from the so-= lution. The2-methyl-3-methoxypyridine-a5-dis carboxylic' anhydride is thus obtainedas an oil which distils at a temperature of 100 C. in the heating-bathand under 0.1 mm. pressure as a colorless oil which upon rubbing at oncesolidifies to crystals. It melts at 65-67 0. By treatment of thisanhydride with a small quantity of water the 2-methyl3-methoxypyridine-4.5-dicarboxylic acid is obtained herefrom which afterrecrystallization from water melts at 218 C. while foaming up.

W e claim:

1. The process which comprises nitrating a 3 alkoxy--quinaldine--carboxylic acid by means of a nitrating agent, reducing thebz-nitro-B-alkoxy-quinaldine-a-carboxylic acid to the correspondingbz-amino compound by a reducing agent, converting the amine compoundinto a 2 methyl 3 alkoxy pyridine 4.5.6 tricarboxylic acid by oxidation,and decarboxylating the latter product to a Z-methyl-B-alkoxypyridine-abdicarboxylic acid compound by heat treatment.

2. The process which comprises nitrating a 3-methoxy-quinaldine-i-carboxylic acid by means of a nitrating agent,reducing the bz-nitro-3- methoxy-quinaldinei-carboxylic acid to thecorresponding bz-amino compound by a reducing agent, converting theamino compound into a 2- methyl 3 methoxy pyridine 4.5.6 tricarboxylicacid by oxidation, and decarboxylating the latter product to aZ-methyl-S-methoxy pyridine-j-dicarboxylic acid compound by heattreatment.

a nitrating agent, reducing the bz-nitro-3-a1-koxy-quinaldine-l-carboxylic acid to the corresponding bz-amino compoundby a reducing agent, converting the amino compound into a 2- methyl 3alkoxy pyridine -.4.5.6 tricarboxylic acid by oxidation withpermanganate in the presence of alkali and decarboxylating the latterproduct to a 2-methyl-3-alkoxy pyridine-4.5-dicarboxylic acid compoundby heat treatment.

4. The process which comprises nitrating a 3-methoxy-quinaldine-4-carboxylic acid by means of a mtrating .agent,reducing the bz-nitro-3- methoxy-qumaldine-4-carboxylic acid to thecorresponding bz-amino compound by a reducing agent, converting theamino compound into a72- methyl-B-methoxy pyridine-4.5.G-tricarboxylicacid by oxidation with permanganate in the presence of alkali anddecarboxylating the latter product to a 2-methyl-3-methoxy pyridine-4.5-dicarboxylic acid compound by heat treatment.

5. The process which comprises nitrating a 3-aJkoxy-quinaldine--oarboxylic acid by means of a nitrating agent,reducing the bz-nitro-3-alkoxyquinaldine-i-carboxylic acid to thecorresponding bz-amino compound by a reducing agent, converting theamino compound into a 2-methyl-3- alkoxy pyridine-4.5.6-tricarboxylicacid by oxidation, and decarboxylating the latter product to a.2-methyl-3 -alkoxy pyridine-4.5-dicarb'oxylic acid compound by heattreatment above 100 C. in the presence of a diluent.

6. The process which comprises nitrating a 3-alkoxy-quinaldine-l-carboxylic acid by means of a nitrating agent,reducing the bz-nitro-3-alkoxyquinaldine-4-carboxylic' acid to thecorresponding bzsamino compound by a reducing agent, converting theamino compound into a 2-methyl-3-alkoxy pyridine-4.5.6-tricarboxylicacid by oxidation with permanganate in the presence of alhali anddecarboxylating the latter product to a Z-methyl-S-alkoxyPyridine-4.5-dicarboxylic acid compound by heat treatment above 100 C.in the presence of a diluent. 1

7. The process which comprises nitrating a 3-methoxy-quinaldine-a-carboxylic acid by means of, a mtrating agent,reducing the bz-nitro-3- methoxy-quinaldine--carboxylic acid to thecorresponding bz-amino compound by a reducing agent, converting theamino compound into a 2- methyl-B-methoxy pyridine-4.5.6-tricarboxylicacid by oxidation with permanganate in the presence of alkali anddecarboxylating the latter product to a 2-methyl-3-methoxy Pyridine-5-dicarboxylic acid compound by heat treatment above 100 C. in thepresence of a diluent.

8. The process which comprises nitrating a 3methoxy-quinaldine-i-carboxylic acid by means of a nitrating mixture ofnitric and sulfuric acid,

reducing the bz-nitro-3-methoxy-quinaldine-4- carboxylic acid to thecorresponding bz-amino compound while using iron as the reducing agent,

converting the amino compound into a 2-methyl- B-methoxypyridine-4.5.G-tricarboxylic acid by oxidation with permanganate in thepresence of alkali and decarboxyiating the latter product to aZ-methyl-Ii-methoxy pyridine-4.5-dicarboxylic acid compound by heattreatment above C. in the presence of a. diluent.

9. The process which comprises nitrating a 3- methoxy-quinaldine-4carboxylic acid by means of a nitrating mixture of nitric and sulfuricacid, reducing the bz-nitro-3-methoxy-quinaldine-4- carboxylic acid tothe corresponding bz-amino compound while using iron as the reducingagent, converting the amino compound into a Z-methyl- 3-methoxypyridine-4.5.6-tricarbbxylic acid by oxidation with permanganate in thepresence of alkali and decarboxylating the latter product to a2-methy1-3-methoxy pyridine-4.5-dicarboxylic acid compound by boilingwith acetic anhydride.

10. The process of producing a. 2-methyl-3-methoxypyridine-45-dicarboxylic. acid which comprises oxidizing abz-amino-S-methoxyquin- 'aidine-i-carboxylic acid into a2-methyl-3-methoxypyridine-4.5.6-trlcarbo lic acid and decarboxylatingthe latter prod at by heat treatment to a2-methy1-3-methoxypyridine-4.5-dicarbox- 5 yiic acid.

WALTER SALZER. HANS HENECKA.

